Asymmetric catalysis based on chiral phospholanes and hydroxyl phospholanes

ABSTRACT

Chiral phosphine ligands derived from chiral natural products including D-mannitol and tartaric acid. The ligands contain one or more 5-membered phospholane rings with multiple chiral centers, and provide high stereoselectivity in asymmetric reactions.

BACKGROUND OF THE INVENTION

[0001] This application is a Continuation-In-Part of and claims priorityfrom U.S. application Ser. No. 09/377,065, filed on Aug. 19, 1999 andclaims priority from U.S. Provisional Application Serial No. 60/097,473,filed on Aug. 21, 1998.

[0002] 1. Field of the Invention

[0003] This invention relates to chiral phospholanes derived fromnatural products, and asymmetric catalysis using these phospholanes.

[0004] 2. Description of Related Art

[0005] Many chiral phosphine ligands have been explored for practicalapplication in asymmetric catalysis, but few chiral ligands or motifsare efficient for the synthesis of commercially useful chiral moleculesin industry.

[0006] Among known chiral phosphines, several are made fromelectron-donating chiral phospholanes. One example is the Brunnerphospholane shown below. Brunner, H., Organometal. Chem. (1987) 328, 71.However, poor enantioselectivities were observed.

[0007] The ligands DuPhos™ and BPE have been used effectively forcertain asymmetric hydrogenation reactions. See U.S. Pat. Nos.5,329,015; 5,202,493; and 5,329,015; Burk, M. J., J. Am. Chem. Soc.(1991) 113, 8518; Burk, M. J., J. Am. Chem. Soc. (1993) 115, 10125;Burk, M. J., J. Am. Chem. Soc. (1996) 118, 5142. These ligands, however,are not effective for some other asymmetric reactions. Moreover,synthesis of these ligands can be difficult, involving a tedious Kolbereaction. Also, several liquid DuPhos™/BPE ligands are air-sensitive andtherefore difficult to handle.

[0008] The chiral phosphine RoPhos and its use in Rh-catalyzedasymmetric hydrogenation have been reported. Holz, J. et al., A. J. Org.Chem. (1998) 63, 8031; EP 0889 048. Chiral phosphine X1 has also beenreported. Carmichael, D. et al., Chem. Commun. (1999) 261. However, thesynthesis is tedious, involving a P stereogenic center.

[0009] The inventor has found that it was not possible to make hydroxyanalogs of RoPhos using the experimental procedure disclosed in J. Org.Chem. (1998) 63, 8031. A new synthetic route has been developed. Uniqueproperties are associated with hydroxylphospholanes. An efficient routeto these compounds has also been developed by this inventor. Based onthis hydroxylphospholane framework, a polymer chain or a soluble speciessuch as SO₃, PO₃ ²⁻, (CH₂CH₂O)_(n)CH₂CH₂OH (n=1, 2, 3) can beintroduced.

SUMMARY OF THE INVENTION

[0010] One aspect of the invention is a ligand of formula A, A′, B, B′,C, C′, D, or D′, or the corresponding enantiomer:

[0011] Another aspect of the invention is a compound of the formula E:

[0012] Another aspect of the invention is a catalyst including one ofthe compounds A-E above, wherein the compound is in the form of acomplex with a transition metal.

[0013] Another aspect of the invention is a process for preparing acompound of formula B, by reacting a compound of formula B^(x) with aphosphine:

[0014] Another aspect of the invention is a process that includessubjecting a substrate to an asymmetric reaction in the presence of oneof the above-described ligands, wherein said asymmetric reaction is ahydrogenation, hydride transfer, hydrosilylation, hydroboration,hydrovinylation, olefin metathesis, hydroformylation,hydrocarboxylation, allylic alkylation, cyclopropanation, Diels-Alder,Aldol, Heck, [m+n] cycloaddition, or Michael addition reaction.

[0015] Accordingly, one advantage of the invention is in providingchiral ligands that can be made in large scale from inexpensive naturalproducts such as D-mannitol or tartaric acids. Another advantage is inproviding new chiral ligands A′-D′ in FIG. 3, in which the relativeconfiguration of the four stereogenic centers around the phospholanediffers from A-D.

[0016] Yet another advantage is in providing chiral ligands that aresolid and/or more air-stable due to added functional groups, and aremore easily handled compared to air-sensitive liquids such asDuPhos™/BPE ligands. Yet another advantage is in providing chiralligands that have functional groups on the phospholanes that can be keystereochemistry-defining groups, such as a hemilabile anchor, a hydrogenbonding source, or a cation binding site through a crown ether. Yetanother advantage is in providing chiral ligands that have additionalfunctional groups on the phospholanes with water-soluble properties anda convenient site to link a polymer support.

[0017] Yet another advantage of the invention is in providing catalystsfor a variety of asymmetric reactions such as hydrogenation, hydridetransfer reaction, hydrosilylation, hydroboration, hydrovinylation,olefin metathesis, hydroformylation, hydrocarboxylation, allylicalkylation, cyclopropanation, Diels-Alder reaction, Aldol reaction, Heckreaction, Baylis-Hillman reaction and Michael addition can be exploredbased on these innovative ligand systems.

[0018] Yet another advantage of the invention is in providing a varietyof methods to make both enantiomers of chiral phosphines. BesidesD-mannitol, other chiral pool materials such as D and L-tartaric acidscan also be used as suitable starting materials for ligand synthesis.Only one phospholane enantiomer can be conveniently obtained usingD-mannitol as the starting material while both phospholane enantiomerscan be easily obtained when using D and L-tartaric acids for the ligandsynthesis.

[0019] Both the foregoing general description and the following detaileddescription of the invention are exemplary and explanatory only and arenot necessarily restrictive of the claimed invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020]FIG. 1 shows new chiral ligands A, A′, B, B′, C, C′, D, and D′ ofthe invention.

[0021]FIGS. 2A-2F shows the structure of ligand examples L1 to L32.

[0022]FIGS. 3A-3C illustrate syntheses of ligands L1 to L32.

[0023]FIGS. 4A-4C show syntheses of some chiral 1,4-diols.

DETAILED DESCRIPTION OF THE INVENTION

[0024] The following definitions are used. Other abbreviations wellknown to persons of skill in the art of asymmetric synthesis are alsoused in this specification.

[0025] % ee: enantiomeric excess, (% S−% R)/(% S+% R) or (% R−% S)/(%S+% R)

[0026] acac: acetylacetonate

[0027] Bn: benzyl

[0028] COD: 1,5-cyclooctadiene

[0029] Cy: cyclohexyl

[0030] DBA: dibenzylideneacetone

[0031] HMPA: hexamethylphosphoramide

[0032] Ipc: isopinocampheyl

[0033] MOM: methoxymethyl

[0034] Otf: trifluoromethanesulfonate

[0035] rt: room temperature

[0036] TBDMSCL: t-butyldimethylsilyl chloride

[0037] Im: imidazole

[0038] The chiral ligands of the present invention may contain alkyl andaryl groups. By alkyl is meant any straight, branched, or cyclic alkylgroup. The number of carbons in the alkyl group is not particularlylimited. Preferably, alkyl refers to C1-C20, more preferably C₁-C₈, evenmore preferably C₁-C₄ alkyl groups. Examples of such alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, andisomers of heptyl, octyl, and nonyl. Alkyl groups may be substitutedwithout particular restriction, provided that the substituents do nothave an adverse effect on the asymmetric reaction, and are inert to thereaction conditions or are thereby converted in a desirable manner.Examples of such substituents include, but are not limited to, aryl,heterocyclo, alkoxy, halo, haloalkyl, amino, alkylamino, dialkylamino,nitro, amido, and carboxylic ester groups, and any suitable combinationthereof.

[0039] By aryl is meant any aromatic or heteroaromatic ring, includingsuch rings fused to other aliphatic, aromatic or heteroaromatic rings.Examples of aromatic rings include, but are not limited to, phenyl,naphthyl, anthryl, fluorenyl, indenyl, and phenanthryl. Heteroaromaticrings may contain one or more heteroatoms, preferably one or more atomsof nitrogen, oxygen, or sulfur. Examples of heteroaromatic ringsinclude, but are not limited to, pyrrole, pyridine, quinoline,isoquinoline, indole, furan, and thiophene. Aryl groups may besubstituted without particular restriction, provided that thesubstituents do not have an adverse effect on the asymmetric reaction,and are inert to the reaction conditions or are thereby converted in adesirable manner. Examples of such substituents include, but are notlimited to alkyl, aryl, heterocyclo, alkoxy, halo, haloalkyl, amino,alkylamino, dialkylamino, nitro, amido, and carboxylic ester groups, andany suitable combination thereof.

[0040] The optical purity of the ligand is preferably at least about 85%ee, more preferably at least about 90% ee, more preferably at leastabout 95% ee, even more preferably at least about 98% ee, and even morepreferably about 100% ee.

[0041] As is well known to a person skilled in the art of asymmetricsynthesis, a chiral ligand can exist as two enantiomers of oppositeconfiguration. A person skilled in the art will recognize that for anygiven asymmetric reaction, each enantiomer will produce products ofopposite configuration from the other, but with the same conversion andoptical purity. In this specification, ligand and product structures areshown for one enantiomer for convenience. Of course, the disclosure alsoapplies to the corresponding enantiomers of opposite configuration, anda person skilled in the art can select the appropriate enantiomer toachieve the desired product configuration.

[0042]FIG. 1 shows several classes of chiral phospholanes (A, B, C, D,and A′, B′, C′, D′). The difference between A, B, C, D, and A′, B′, C′,D′ is in the inversion of two chiral centers in the middle of the rings.For each class of ligands, enantiomers are also included, which can bemade through different chiral pools. A and A′ are chiral bidentatephospholanes with four chiral centers. B and B′ are chiral bidentatephospholanes with four chiral centers and linked by a ring in the middleof five membered rings. C, D, C′, D′ are monophospholanes.

[0043] Examples of chiral phospholanes according to the inventioninclude, but are not limited to those shown in FIG. 2. Ligand L1 (A) hasa benzyl protecting group on the two center hydroxyl groups while ligandL3 has a hydroxyl group. Ligand L2 belongs to class B′ with a cyclicketyl in the center. Ligands L1-L13 contain bridging groups such asCH₂CH₂, benzene, ferrocene, biaryl, binaphthyl groups. Ligands L14-L17are linked to a polymer backbone. Ligands L18-L21 have water solublegroups. In ligands L22-L25, an 18-crown-6 group was introduced. LigandsL26-L27 are monophospholanes containing a variety of groups. LigandsL30-L32 have additional groups as substituents of aryls; some will leadto hemilabile ligands.

[0044] One embodiment of the invention is a compound of formula A, A′,B, B′, C, C′, D, or D′, or the corresponding enantiomer:

[0045] wherein:

[0046] a) R and R² are aryl, alkyl, alkyl aryl, or aryl alkyl, which maybe substituted with carboxylic acid, alkoxy, hydroxy, alkylthio, thiol,dialkylamino, diphenylphosphino, or chiral oxazolino groups;

[0047] b) R¹ can be H, alkyl, silane, aryl, a water soluble unit, or alinked polymer chain or inorganic support;

[0048] c) the ring component O

O represents a protected diol, a crown ether linkage, —O-alkyl-O—wherein the alkyl group is linked to a polymer, or —O—(CH₂CH₂—O)_(n)—wherein the methylene groups are optionally substituted by C₁-C₈ alkyl;and

[0049] d)

[0050]  may be:

[0051] —(CH₂)_(n)— where n is an integer ranging from 1 to 8;

[0052] —(CH₂)_(n)X(CH₂)_(m)— wherein n and m are each integers, the sameor different, ranging from 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴,divalent aryl, divalent fused aryl, divalent 5-membered ringheterocyclic group, or divalent fused heterocyclic group, wherein R⁴ ishydrogen, aryl alkyl, substituted aryl or substituted alkyl groups; or

[0053] 1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl or 2,2′-divalent1,2′binapthyl or ferrocene, each of which may be substituted with aryl,C₁-C₈ alkyl, F, Cl, Br, 1, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵₂, AsR⁵ ₂, or SbR⁵ ₂, wherein:

[0054] the substitution on 1,2-divalent phenyl, the ferrocene or biarylbridge can be independently halogen, alkyl, alkoxyl, aryl, aryloxy,nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonic acids; and

[0055] R⁵ is hydrogen, C1-C8 alkyl, C₁-C₈ fluoroalkyl, or C₁-C₈perfluoroalkyl, aryl; substituted aryl; arylalkyl; ring-substitutedarylalkyl; or —CR³ ₂(CR³ ₂)_(q)X(CR³ ₂)_(p)R¹ wherein q and p areintegers, the same or different, ranging from 1 to 8; R³ is an aryl,alkyl, substituted aryl and substituted alkyl group; and R¹ and X are asdefined above.

[0056] The term “water soluble unit” means any functional groupimparting water solubility, including, but not limited to, SO₃, PO₃ ²;CH₂COO, a quaternary ammonium group attached via an ester or alkyllinkage such as C═O(CH₂)_(n)NAlk₃ or (CH₂)_(n)NAlk₃ where Alk₃represents three alkyl groups that are independently C₁-C₄ alkyl and xis 1-4, (CH₂CH₂O)_(n)CH₂CH₂OT (n=1-3) wherein T may be H or CH₃, i.e.,PEG or MeO-PEG. The counterion for water soluble units bearing a chargeinclude, but are not limited to, metals such as alkali and alkalineearth metals, and halogens and Otf.

[0057] When R¹ is a linked polymer chain, the linker may be any suitablelinking unit commonly used to bind catalysts to polymers or supportmaterials, including, but not limited to, a C₁-C₆ branched or unbranchedalkyl chain, —C₆H₄CH═CH₂ for polymerization with styrene or othersubstituted vinyl monomer, —C═OCH═CH₂ for polymerization with anacrylate or other substituted vinyl monomer. The polymer may be anypolymer or copolymer, preferably polystyrene or a copolymer of styreneand a substituted vinyl monomer, polyacrylate, PEG or MeO-PEG, ordendritic polymers of polyesters or polyenamides. The preceding alsoapplies to the ring component

[0058] as —O-alkyl-O— wherein the alkyl group is linked to a polymer.

[0059] When R¹ is a linked inorganic support, examples of inorganicsupports include, but are not limited to, silica or zeolites. Theinorganic support may be linked by any conventional means, including,but not limited to, attaching —C═ONH(CH₂)_(n)Si(OEt)₃ (where x is 1-4)as linker and binding through this linker to silica via controlledhydrolysis of the Si(OEt)₃ group, where C═ONH may be replaced by anyother functional group suitable for connecting the methylene chain ofthe linker to the phospholane oxygen.

[0060] When the ring component O

O is a protected diol, a person of skill in the art will recognize thatany number of the diol protecting group may be used, e.g., thosedescribed in Greene and Wuts, Protective Groups in Organic Synthesis,1991, John Wiley & Sons, and MacOmie, Protective Groups in OrganicChemistry, 1975, Plenum Press, the entire contents of which areincorporated herein by reference. A suitable diol protecting group maybe deprotected under conditions that do not significantly degrade therest of the molecule. Examples of diol protecting groups include, butare not limited to acetals and ketals.

[0061] In one variant, the invention is a compound of formula A or A′,or the corresponding enantiomer. Preferably, in the compound of formulaA or A′, or the corresponding enantiomer, R is methyl, ethyl, or benzyl,R¹ is hydrogen or benzyl, and

[0062] is —(CH₂)_(n)— where n is an integer ranging from 1 to3,1,2-divalent phenyl; 2,2′-divalent 1,1′biphenyl, 2,2′-divalent1,2′binapthyl, or ferrocene, each of which may be substituted with alkylhaving 1-3 carbon atoms; or OR⁵, wherein R⁵ is methyl or ethyl.

[0063] Examples of the compound of formula A or A′ include, but are notlimited to L1, L3-L5, L7-L8, L10-L12, and L18-L21, and the correspondingenantiomers, and the compound of formula 2 below and its enantiomer.

[0064] In another variant, the invention is a compound of formula B orB′, or the corresponding enantiomer. Preferably, in the compound offormula B or B′, or the corresponding enantiomer, R is C1-C4 alkyl,unsubstituted or substituted by phenyl or OR⁵, wherein R⁵ is C₁-C₂alkyl, and the ring component O

O is —O—CR^(a)R^(b)—O—, wherein R^(a) is hydrogen or C1-C4 alkyl andR^(b) is an alkyl or aryl linker attached to a polymer.

[0065] Examples of the compound of formula B or B′ include, but are notlimited to L2, L6, L9, L13, L14-L17, and L22-L25, and the correspondingenantiomers, and the compound of formula 3 below and its enantiomer:

[0066] In another variant, the invention is a compound of formula C, D,C′, or D′, or the corresponding enantiomer. Preferably, in the compoundof formula C, D, C′, or D′, or the corresponding enantiomer, R ismethyl, ethyl, or benzyl; R¹ is hydrogen or benzyl; R² is o-X-phenylwherein X is a carboxylic acid, alkoxy, hydroxy, alkylthio, thiol,dialkylamino, diphenylphosphino, or chiral oxazolino group; and the ringcomponent

[0067] is —O—CR^(a)R^(b)—O—, wherein R^(a) and R^(b) are independentlyhydrogen or C1-C4 alkyl.

[0068] Examples of the compound of formula B or B′ include, but are notlimited to structures L26-L32, and the corresponding enantiomers, andthe compound of formula 1 below and its enantiomer:

[0069] Another embodiment of the invention is a compound of formula E orthe corresponding enantiomer.

[0070] wherein:

[0071] R and R⁹ are aryl, C1-C8 alkyl, C1-C8 alkyl aryl, or aryl C1-C8alkyl, which may be substituted with carboxylic acid, alkoxy, hydroxy,alkylthio, thiol, dialkylamino; diphenylphosphino, or chiral oxazolinogroups; and

[0072] W is boron, phosphorus, or silicon, or W and R⁹ together form C═Oor SO₂.

[0073] Preferably, in the compound of formula E or the correspondingenantiomer, R is C₁-C₄ alkyl and R⁹ is C1-C4 alkyl or phenyl.

[0074] Another embodiment of the invention is a catalyst including anyof the compounds described in the embodiments above, wherein thecompound is in the form of a complex with a transition metal. Inprinciple, any transition metal may be used. Preferably, the transitionmetal is a Group VIII transition metal. More preferably, the transitionmetal is rhodium, iridium, ruthenium, nickel, or palladium. Preferably,the compound is in the form of a complex with Pd₂(DBA)₃, Pd(OAc)₂;[Rh(COD)Cl]₂, [Rh(COD)₂]X, Rh(acac)(CO)₂; RuCI₂(COD),Ru(COD)(methylallyl)₂, Ru(Ar)Cl₂, wherein Ar is an aryl group,unsubstituted or substituted with an alkyl group; [Ir(COD)Cl]₂,[Ir(COD)₂]X; or Ni(allyl)X; wherein X is a counterion. The counterion Xmay generally be any suitable anion for use in asymmetric synthesis. Aperson of skill in the art can readily determine what such a suitablecounterion would be for any particular set of ligands, reactionconditions and substrates. Examples of suitable counterions include, butare not limited to, halogen ions (including Cl⁻, Br⁻, and I⁻), BF₄ ⁻,ClO₄ ⁻, SbF₆ ⁻, CF₃SO₃ ⁻, BAr₄ ⁻ (wherein Ar is aryl), and Otf⁻(trifluoromethanesulfonate). Preferably, X is BF₄, ClO₄, SbF₆, orCF₃SO₃. Preferably, the catalyst comprises Ru(RCOO)₂(diphosphine),RuX₂(diphosphine), Ru(methylallyl)₂(diphosphine), or Ru(arylgroup)X₂(diphosphine), and X is halogen.

[0075] A non-limiting example of the invention is a catalyst forasymmetric hydrogenation of ketones, imines, and olefins, that includesRh complexes [Rh(COD)Cl]₂, [Rh(COD)₂]_(x) (X BF₄, ClO₄, SbF₆, CF₃SO₃,etc.)] with 2 or 3:

[0076] Another embodiment of the invention is a process includingsubjecting a substrate to an asymmetric reaction in the presence of acatalyst comprising a chiral ligand according to claim 1, wherein saidasymmetric reaction is a hydrogenation, hydride transfer,hydrosilylation, hydroboration, hydrovinylation, olefin metathesis,hydroformylation, hydrocarboxylation, allylic alkylation,cyclopropanation, Diels-Alder, Aldol, Heck, [m+n] cycloaddition, orMichael addition reaction. Preferably, the process includes asymmetrichydrogenation of a ketone, imine, enamide, or olefin.

[0077] Another embodiment of the invention is a process for preparing acompound of formula B, comprising reacting a compound of formula B^(x)with a phosphine:

[0078] wherein:

[0079]  the phosphine is

[0080]  ;

[0081] a) R is aryl, alkyl, alkyl aryl, or aryl alkyl, which may besubstituted with carboxylic acid, alkoxy, hydroxy, alkylthio, thiol,dialkylamino, diphenylphosphino, or chiral oxazolino groups;

[0082] b) the ring component

[0083]  represents a protected diol, a crown ether linkage, or—O—CH₂CH₂)_(n)—O— wherein n is an integer ranging from 1 to 8 and themethylene groups are optionally substituted by alkyl or linked to apolymer; and

[0084] c)

[0085]  may be:

[0086] —(CH₂)_(n)— where n is an integer ranging from 1 to 8;

[0087] —(CH₂)_(n)X(CH₂)_(m)— wherein n, m are each integers, the same ordifferent, ranging from 1 to 8; or

[0088] 1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl or 2,2′-divalent1,2′binapthyl or ferrocene, each of which may be substituted with arylor substituted aryl, or alkyl having 1-8 carbon atoms, heteroatom groupssuch as F, Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂,AsR⁵ ₂, or SbR⁵ ₂, wherein:

[0089] the substitution on 1,2-divalent phenyl, the ferrocene or biarylbridge can be independently halogen, alkyl, alkoxyl, aryl, aryloxy,nitro, amino, vinyl, substituted vinyl, akkynyl, or sulfonic acids; and

[0090] R⁵ is hydrogen, C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, or C₁-C₈perfluoroalkyl, aryl; substituted aryl; arylalkyl; ring-substitutedarylalkyl; or —CR³ ₂(CR³ ₂)_(q)X(CR³ ₂)_(p)R¹ wherein q and p areintegers, the same or different, ranging from 1 to 8; X is O, S, NR⁴,PR⁴, AsR⁴, SbR⁴, divalent aryl, divalent fused aryl, divalent 5-memberedring heterocyclic group, or divalent fused heterocyclic group, whereinR³ and R⁴ are aryl, alkyl, substituted aryl and substituted alkylgroups.

[0091] Preferably, R is C₁-C₄ alkyl; the ring component

[0092] represents a protected diol; and

[0093] is unsubstituted or substituted 1,2-divalent phenyl. Moreprefarbly, R is methyl or ethyl, the ring component

[0094] is —O—C(CH₃)₂—O—, and

[0095] is unsubstituted 1,2-divalent phenyl.

[0096]FIGS. 3A-3C show several pathways for the synthesis of compoundsshown in FIGS. 2A-2F. The chiral 1,4-diols used in the synthesis ofligands L1-L32 can be derived from D-mannitol and related compounds. Anumber of these diols have been reported in the literature. Theprocedure for the synthesis of L1(A), L3(A) and L8 (A′) is outlined inFIGS. 3A-3B; key intermediates L35 and L35′ have been reported in theliterature (Poitout, L.; Tetrahedron Letter (1994) 35, 3293). Theepoxide opening step from L35 to L37 in FIG. 3A has also been reported(Nugel, S. et al. J. Med. Chem. (1996) 39, 2136). Formation of cyclicsulfates can be done according Sharpless' procedure (Kim, B. M.,Tetrahedron Letters (1989) 30, 655). The last step is similar as thesynthesis of DuPhos™ (Burk, U.S. Pat. Nos. 5,329,015; 5,202,493; and5,329,015; Burk, M. J., J. Am. Chem. Soc. (1991) 113, 8518; Burk, M. J.,J. Am. Chem. Soc. (1993) 115, 10125; Burk, M. J., J. Am. Chem. Soc.(1996) 118, 5142). In the step to form L37, other nucleophiles such asCH₃ ⁻, Cy⁻ can be applied other than Ph⁻. Intermediate L36 can beobtained easily. In principle, ketyl can be formed from L3(A) to giveclass B compounds.

[0097] When para-vinyl benzaldehyde is used as the protecting group,polymerization under polystyrene forming conditions should yieldcompound L17 (B), shown in FIG. 2C.

[0098] Instead of using a benzyl protecting group, 18-crown-6 or watersoluble groups can be linked to form compounds such as L19 (A) or L25(B), as shown in FIGS. 2D and 2E, respectively.

[0099] Another epoxide L39 has been studied extensively for thesynthesis of HIV protease inhibitors (Ghosh, A. K., Tetrahedron Lett.(1991) 32, 5729. and Nugel, S. et al., J. Med. Chem. (1996) 39, 2136).Compound LAO is known and conversion of this intermediate to L9 (B) isexpected. Finally, intermediate L41 and L38 can be converted to L29 (C)as illustrated in FIG. 6.

[0100]FIGS. 4A-4C outline some useful synthetic procedures, which wasrecently disclosed in the literature. Instead of using D-mannitol as thestarting material, which can only lead to one enantiomer of the chiralphosphine, preparation of chiral diols from either D or L-tartaric estercan result in formation of either of two enantiomers. Using thesereported procedures (Nugel, S. et al. J. Med. Chem. (1996) 39, 2136;Colobert, F. J. Org. Chem. (1998) 63, 8918; and Iwasaki, S. TetrahedronLett. (1996) 37, 885), several chiral 1,4-diols can be obtained, asshown in FIGS. 4A-4C.

[0101] The present invention is further illustrated by the followingexamples, which are designed to teach those of ordinary skill in the arthow to practice the invention. The following examples are illustrativeof the invention and should not be construed as limiting the inventionas claimed.

EXAMPLES

[0102] Synthesis of Phospholane Ligands

[0103] The hydroxyl phosphine ligands 1, 2, and 3 were synthesizedsuccessfully in high yield using familiar procedures. They are whitesolids. The synthetic route is exemplified below.

[0104] Compound 10 is a nice colorless crystal and can be recrystallizedfrom ethyl ehter and methanol. Compound 2 was used directly afterremoval of the reaction solvent without any purification. An advantageof this route is that there is no need to run column chromatography forpurification.

[0105] Compound 14 is a colorless crystal and can be recrystallized fromethyl ether and methanol.

[0106] Compound 3 was used directly after removal of the reactionsolvent without any purification. There is no need to run a column inthis synthetic route. Ring opening of 11 with other nucleophiles R₂CuLi(R=Ph, Et, iPr etc.) leads to a series of compounds.

[0107] The cyclic sulfate 15 was also made from the correspondingalcohol, which was synthesized in the same procedure to make 12.

[0108] Ligand 16 can be made in a similar manner using the sameprocedure as for the synthesis of 2 and 3.

[0109] Compound 18 was prepared by stirring 1 and phenylboronic acid inmethylene chloride. After removal of the solvent, it was used directlyin asymmetric reaction.

[0110] Compound 19 was prepared from cyclic sulfate 9. Acid catalytichydrolysis afforded the hydroxylphosphine 1 in high yield (>90%).

[0111] Compound 21 was prepared from known cyclic sulfate 20. Severalchiral monophospholanes from D-mannitol (e.g., 19, 21) are made and manymethods cleave the protecting groups to give hydroxylphospholane 1. Theiso-propylene group in 19 was smoothly removed by an acid catalyzedhydrolysis. However, the borane adduct of 21 was just selectivelydebenzylated when BCl₃ or BF₃.Et₂O was used as the reagent to give thederivatives bearing one hydroxyl and one benzyl ether group.Hydrogenation of 21 using Pd/C catalyst does not give the desiredhydroxyl phospholane product 1. The corresponding phosphine oxide of 21also gave selectively debenzylated products under mild hydrogenationconditions (10% Pd(OH)₂/C). The hydrogenation reaction done under hightemperature (50° C.) and H₂ pressure (40 atm) not only cleaved thebenzyl ether but also reduced the phenyl group to a cyclohexyl group.

[0112] General Experimental Procedure

[0113] Unless otherwise indicated, all reactions were carried out undernitrogen. THF and ether were freshly distilled from sodium benzophenoneketyl. Toluene were freshly distilled from sodium. Dichloromethane andhexane were freshly distilled from CaH₂. Methanol was distilled frommagnesium and CaH₂. Reactions were monitored by thin-layerchromatography (TLC) analysis. Column chromatography was performed usingEM silica gel 60 (230400 mesh).

[0114]¹H NMR were recorded on Bruker ACE 200, WP 200, AM 300 and WM 360spectrometers. Chemical shifts are reported in ppm downfield fromtetramethylsilane with the solvent resonance as the internal standard(CDCl₃, δ 7.26 ppm). ¹³C, ³¹P and ¹H NMR spectra were recorded on BrukerAM 300 and WM 360 or Varian 200 or 500 spectrometers with completeproton decoupling. Chemical shifts are reported in ppm downfield fromtetramethylsilane with the solvent resonance as the internal standard(CDCl₃, δ 77.0 ppm). Optical rotation was obtained on a Perkin-Elmer 241polarimeter. MS spectra were recorded on a KRATOS mass spectrometer MS9/50 for LR-EI and HR-EI. GC analyses were carried out on aHewlett-Packard 5890 gas chromatograph with a 30-m Supelco β-DEX™column. HPLC analyses were carried out on a Waters™ 600 chromatographwith a 25-cm CHIRALCEL OD column.

EXAMPLE 1 Phosphine 19

[0115] To a stirred solution of phenylphosphine (0.44 g, 4.0 mmol) inTHF (80 mL), n-BuLi (1.6 M n-hexane solution, 2.5 mL, 4.0 mmol) wasadded dropwise via a syringe at −78° C. The resulting pale yellowsolution was stirred for further 2 h at room temperature. After coolingthe mixture to −78° C., cyclic sulfate 9 (1.01 g, 4.0 mmol) in THF (40mL) was added over 10 min. The resulting yellow solution was warmed toroom temperature and stirred for 4 h. After cooling to −78° C., n-BuLi(1.6 M solution in n-hexane, 2.5 mL, 4.0 mmol) was added, and thereaction mixture was stirred for an additional 20 h at room temperature.The color of the reaction mixture changed from orange yellow to red, andthen decolorized to colorless. After removal of the solvent underreduced pressure, the residue was dissolved in 40 mL of ethyl ether, and30 mL of brine was added. The aqueous layer was then washed with 3×30 mLethyl ether. The combined organic layers were dried over Na₂SO₄ andconcentrated to afford a colorless oil. This oil can be further purifiedby a short silica gel column eluted with hexane/ether (9:1), ¹H NMR(CDCl₃): δ 7.72-7.27 (m, 5H, aromatic), 4.604.32 (m, 2H), 2.70-2.51 (m,2H), 1.52 (s, 6H), 1.38-1.32 (m, 3H), 0.70-0.52(m, 3H). ³¹P NMR (CDCl₃):δ 50.2 ppm.

EXAMPLE 2 Phosphine 1

[0116] Phosphine 19 obtained above was dissolved in 50 mL methanol and 2mL of water. To this solution, 0.05 mL of methanesulfonic acid was addedand the resulting mixture was refluxing for 10 h. The solvent wasremoved under reduced pressure and the residue was dissolved in 50 mL ofmethylene chloride. 30 mL of aq NaHCO₃ was added and the two layers wereseparated. The aqueous layer was washed with 3×40 mL of methylenechloride. The combined organic layers were dried over Na₂SO₄ andconcentrated to give a white solid, compound 1.

EXAMPLE 3 Phosphine 21

[0117] To a stirred solution of phenylphosphine (220.2 g, 2.0 mmol) inTHF (50 mL), n-BuLi (1.6 M n-hexane solution, 1.25 mL, 2.0 mmol) wasadded dropwise via a syringe at −78° C. Then the resulting yellowsolution was stirred for further 2 h at room temperature. After coolingthe mixture to −78° C., cyclic sulfate 20 (0.78 g, 2.0 mmol) in THF (30mL) was added over 10 min. The resulting brown solution was warmed toroom temperature and stirred for 4 h. After cooling to −78° C., n-BuLi(1.6 M solution in n-hexane, 1.25 mL, 2.0 mmol) was added and thereaction mixture was stirred for an additional 20 h at room temperature.Then BH₃-THF complex (1M solution in THF, 3.0 mL, 3.0 mmol) was added at0° C. After stirring overnight, the solvents were removed under reducedpressure. Water (30 mL) was added to the residue and the aqueoussolution extracted with CH₂Cl₂ (3×40 mL). The combined organic layerswere dried (Na₂SO₄) and concentrated to afford the crudephospholane-borane as a colorless syrup. Purification was performed byflash chromatography (hexanes/AcOEt=9:1) to give the 21-borane adduct asa white solid (767 mg, 92%). ¹H NMR (CDCl₃): δ 7.87-7.82 (m, 2H,aromatic), 7.31-7.16 (m, 3H, aromatic), 4.56-4.42 (m, 4H), 4.02-3.90 (m,2H), 2.78-2.72 (m, 2H), 1.22-1.16 (m, 3H), 0.85-0.79 (m, 3H), 1.23-0(broad, 3H, BH₃). ¹³C NMR (CDCl₃): δ 138.0, 137.6, 134.5, 134.4, 131.1,128.5-126.4, 83.7, 83.4, 72.6, 72.3, 36.2, 35.8, 9.2, 9.1. ³¹P NMR(CDCl₃): δ 37.1, b, ppm. The 21-borane adduct was dissolved in 20 mL oftoluene and 2 equivalent of DABCO was added. The resulting mixture washeated at 50° C. for 8 h. After removal of the solvent, the residue waspassed through a plug of silica gel eluted with hexane/ethyl acetate(9:1) to afford phosphine 21 as a colorless oil. ³¹P NMR (CDCl₃): δ 3.8ppm.

EXAMPLE 4 Phosphine 10

[0118] To a stirred solution of 1,2-bis(phosphino)benzene (1.24 g, 8.72mmol) in THF (200 mL), n-BuLi (1.6 M n-hexane solution, 10.9 mL, 17.4mmol) was added dropwise via a syringe at −78° C. Then the resultingyellow solution was stirred for further 2 h at room temperature. Aftercooling the mixture to −78° C., cyclic sulfate 9 (4.39 g, 17.4 mmol) inTHF (50 mL) was added over 10 min. The resulting yellow solution waswarmed to room temperature and stirred for 4 h. After cooling to −78°C., n-BuLi (1.6 M solution in n-hexane, 11.0 mL, 17.5 mmol) was added,and the reaction mixture was stirred for additional 20 h at roomtemperature. After removal of the solvent under reduced pressure, theresidue was dissolved in 50 mL of ethyl ether, and 50 mL of brine wasadded. The aqueous layer was then washed with 3×40 mL ethyl ether. Thecombined organic layers were dried over Na₂SO₄ and concentrated toafford a colorless crystal. This crystal was further recrystallized fromether/methanol. ¹H NMR (CDCl₃): δ 7.38-7.33 (m, 4H, aromatic), 4.464.36(m, 4H), 2.89-2.82 (m, 2H), 2.56-2.51 (m, 2H), 1.47 (s, 6H), 1.42 (s,6H), 1.33-1.28 (m, 6H), 0.73-0.69 (m, 6H); ¹³C NMR (CDCl₃): δ 140.53,130.59, 129.00, 117.44, 81.41, 80.51 (t, J_(PC)=6.5 Hz), 27.34, 27.30,25.05 (t, J_(PC)=10.3 Hz), 24.20, 13.74 (t, J_(PC)=19.6 Hz), 12.15; ³¹PNMR (CDCl₃): δ 45.1 ppm. HRMS calcd for C₂₄H₃₇O₄P₂ (MH⁺) 451.2167; found451.2164.

EXAMPLE 5 Phosphine 2

[0119] Phosphine 10 obtained above was disolved in 100 mL of methanoland 2 mL of water. 0.1 mL of methanesufonic acid was added and theresulting mixturing was refluxing for 10 h. After removal of the solventthe residue was passed through a short plug of silica gel eluted withethyl acetate/methanol (95:5) to give compound 2 as a white solid. ¹HNMR (CD₃OD): δ 8.42-8.07 (m, 2H, aromatic), 7.72-7.69 (m, 2H, aromatic),4.244.17 (m, 4H), 3.31-3.28 (m, 2H), 3.16-3.13 (m, 2H), 1.37-1.30 (m,6H), 0.94-0.88 (m, 6H); ³C NMR (CD₃OD): δ 136.6 (t, J_(PC)=3.4 Hz),133.7, 133.6, 80.2, 80.0, 37.3, 35.4 (d, J_(PC)=10.0 Hz), 11.6 (d,J_(PC)=6.5 Hz), 10.8. ³¹P NMR (CD₃OD): δ 11.9 (broad) ppm. HRMS calcdfor C₁₈H₂₉O₄P₂ (MH⁺) 371.1541; found 371.1523.

EXAMPLE 6 Phosphines 14 and 3

[0120] Phosphine 14 was prepared using the similar procedure for 10 andrecrystallized from ethyl ether/methanol as a colorless crystal. ¹H NMR(CDCl₃): δ 7.41-7.32 (m, 4H, aromatic), 4.504.37 (m, 4H), 2.62-2.61 (m,2H), 2.22-2.20 (m, 2H), 2.19-2.17 (m, 2H), 1.50-1.44 (m, 2H), 1.47 (s,6H), 1.32-1.30 (m, 2H), 0.99-0.95 (m, 6H), 0.88-0.86 (m, 2H), 0.79-0.75(m, 6H); ¹³C NMR (CDCl₃): δ 141.3, 131.1, 129.2, 117.1, 82.3, 81.4 (t,=6.1 Hz), 33.0, 32.8 (t, =9.6), 27.4, 27.3, 21.4, 21.1 (t, =14.2), 14.6,13.1 (t, =5.1 Hz).; ³¹p NMR (CDCl₃): δ 34.5 ppm. Catalytic acidhydrolysis give phosphine 3.

EXAMPLE 7 General Procedure for Asymmetric Hydrogenation

[0121] To a solution of [Rh(COD)₂]X (X=counterion) (5.0 mg, 0.012 mmol)in THF (10 mL) in a glovebox was added chiral ligand (0.15 mL of 0.1 Msolution in toluene, 0.015 mmol). After stirring the mixture for 30 min,the dehydroamino acid (1.2 mmol) was added. The hydrogenation wasperformed at room temperature under hydrogen for 24 h. The reactionmixture was treated with CH₂N₂, then concentrated in Vacuo. The residuewas passed through a short silica gel column to remove the catalyst. Theenantiomeric excesses were measured by GC using a Chirasil-VAL III FSOTcolumn. The absolute configuration of products was determined bycomparing the observed rotation with the reported value. All reactionswent in quantitative yield with no by-products found by GC.

EXAMPLE 8 General Procedure for the Baylis-Hillman Reaction

[0122] The mixture of 4-pyridinecarbonaldehyde (1 mmol) and 1 mL ofmethyl acrylate was degassed three times by a freeze-thaw method, andthen the resulting solution was transferred into another Schlenk tubecontaining 10% catalyst. The solution was stirred at room temperaturefor some time and the methyl acrylate was removed under vaccm. Theresidue was purified by a flash chromatograph eluted with hexanes/ethylacetate (1:2). The enantiomeric excess was measured by capillary GC.

[0123] Asymmetric Baylis-Hillman reaction TABLE 1 CatalyticBaylis-Hillman Reaction

Run Catalyst Reaction Time Yield (%) % ee 1 21 70 h 29 19 2  1  9 h 8317 3 18 31 h 56 18

[0124] The reaction was accelerated significantly when hydroxylphosphinewas used as catalyst. For example, the reaction takes 70 h and giveslower yield (29%) with benzyl protected hydroxylphospholane 21 ascatalyst, while the same reaction proceeds in 9 h and offers high yield(83%) with hydroxylphospholane 1. This demonstrates the importance ofthe hydroxyl group in the catalytic system.

[0125] Hydrogenation of Dehydroamino Acids TABLE 2 AsymmetricHydrogenation of Dehydroamino Acid Derivatives^(a)

Run Substrate Ligand % ee^(b) Ligand % ee 1 R = H, R′ = H 2 >99^(c)3 >99 2 R = H, R′ = CH₃ 2  98.3 3 99 3 R = Ph, R′ = H 2 >99^(c) 3 >99 4R = Ph, R′ = CH₃ 2 >99 3 >99 5 R = p-F—Ph, R′ = H 2  98.5^(c) 3 >99 6 R= p-F—Ph, R′ = CH₃ 2  98.4 3 >99 7 R = p-MeO—Ph, R1 = H 2  98.1^(c,d) 399 8 R = p-MeO—Ph, R′ = CH₃ 2  98.3^(d) 3 >99 9 R = 2-thienyl, R′ = H 2>99^(c) 3 >99 10 R = 2-thienyl, R′ = CH₃ 2 >99 3 >99 11 R = m-Br—Ph, R′= H 3 99 12 R = m-Br—Ph, R′ = CH₃ 3 >99 13 R = o-Cl—Ph, R′ = H 3 98 14 R= o-Cl—Ph, R′ = CH₃ 3 98 15 R = 2-naphthyl, R′ = H 3 >99 16 R =2-naphthyl, R′ = CH₃ 3 >99 17 R = Ph, R′ = H, benzonate 3 >99 18 R = Ph,R′ = CH₃, benzonate 3 >99

[0126] Catalytic Asymmetric Hydrogenation of Itaconic Acid DerivativesTABLE 3 Asymmetric Hydrogenation of Itaconic Acid Derivatives

Run Substrate Ligand % ee Ligand % ee^(a) 1 R = H 2 95.7 3 >99 2 R = CH₃2 97.5 3 >99 3 R = CH₃  3^(b) >99

[0127] Catalytic Asymmetric Hydrogenation of Enamides TABLE 4 AsymmetricHydrogenation of Enamides

Run Substrate Ligand % ee 1 Ar = Ph, R = H 3 95.8 2 Ar = p-MeO—Ph, R = H3 95.3 3 Ar = p-F₃C—Ph, R = H 3 98.1 4 Ar = p-Cy—Ph, R = H 3 97.7

Example 9 Asymmetric Hydrogenation Using Ligand 24

[0128] The Synthetic route to ligand 24 is shown in Scheme 1. From aninexpensive and commerically available starting material, D-mannitol,the important intermediate 1,4-diol cyclic sulfate 9 was preparedaccording to the reported method. See Li, W. et al., Tetrahedron Letter(1999) 40, 6701; Li, W. et al., J. Org. Chem. (2000) 65, 3489; Yan, Y.-Yet al., Org. Letter (2000) 2, 199; Yan, Y.-Y et al., J. Org. Chem (2000)65, 900; merver, Y. L. et al, Heterocycles (1987) 25, 541; Allevi, P. etal., Tetrahedron: Asymmetry (1994) 5, 927; Gao, Y. et al., J. Am. Chem.Soc. (1988) 110, 7538; Kim, B. M. et al., Tetrahedron Letter (1989) 30,655; Holz, J. et al., J. Org. Chem (1998) 63, 8031; Carmichael, D. etal., Chem. Commun. (1999) 261. The 1,1′-bis(phosphino)ferrocene wasprepared from ferrocene through a two-step procedure. See Burk, M. J. etal., Tetrahedron Letter (1994) 35, 9363. Nucleophilic attack of 9 with1,1′-bis(phosphino)ferrocene in the presence of n-BuLi affords ligand24. ¹H NMR (360 MHz, C₆D₆) δ 4.554.50 (m, 2H), 4.344.29 (m, 2H),4.144.12 (m, 4H), 4.05 (m, 2H), 3.72 (m, 2H), 2.38-2.30 (m, 4H),1.51-1.44 (m, 18H), 0.80-0.76 (m, 6H); ¹³C NMR (400 MHz, C₆D₆) δ 117.6(s), 82.3-82.2 (m), 77.4 (d, J_(cp)=37.3 Hz), 75.2 (D J_(cp)=25.3 Hz),72.3 (d, J_(cp)=44.8 Hz), 70.3-70.4 (m), 27.7 (s), 27.6 (s), 26.626.4(m), 14.3(s), 14.0 (s), 11.2 (s); ³¹P NMR (360 MHz, C₆D₆) δ 39.3; mp152-154° C.; HRMS: m/z calcd for C₂₈H₄₀O₄P₂Fe (M+) 559.1829, found559.1846. The new ligand can be easily purified by running columnchromatography in dry-box to give an orange solid in an acceptableyield.

[0129] The Rh(I)-catalyzed hydrogenation of dehydroamino acids and theirester derivatives was performed with ligand 24. The catalytic complexwas prepared in situ by mixing Rh(COD)₂ PF₆ and 24 in solvent. Thecommercially available α-(N-acetamido)acrylate 25a was chosen to screenthe reaction conditions. The results are shown in Table 5. Excellentenantioselectivity (over 99% ee) was observed for this reaction. Thisresult is superior to those obtained with ligand 22 (83% ee) and ligand23 (94% ee). No solvent effect was found. This system works very well inboth polar and non-polar solvents (entries 5-8). In decreasing the H₂pressure from 45 psi to 20 psi and reducing the reaction time to 30 min,no deterioration was observed with respect to either conversion orenantioselectivity. This indicates that this catalytic system is notonly highly enantioselective but also highly efficient. TABLE 5 Rh(I)-24Catalyzed Asymmetric Hydrogenation of α-(N-acetamido)acrylate 25a^(a)

Entry Ligand Solvent Pressure of H₂ (psi) Time (h) ee (%)^(f)  1^(c)22a^(e) MeOH 60 ≧6 64  2^(c) 22b^(e) MeOH 60 ≧6 83  3^(d) 23a^(e) MeOH60 18 69  4^(d) 23b^(e) MeOH 60 18 94 5 6 MeOH 45 3 >99 6 6 DCM 45 3 >997 6 THF 45 3 >99 8 6 Toluene 45 3 >99 9 6 MeOH 45 0.5 >99 10  6 MeOH 200.5 >99 ^(a)Hydrogenation Conditions: The reaction was carried at rt. Insitu catalyst, [Rh(COD)₂PF₆] (1.0 mol %) and 24 (1.1 mol %), was stirredfor 15 min prior to introduction of substrate and H₂. The reaction wentwith 100% conversion. ^(b)The S absolute configration was assigned bycomparison of optical rotation with reported data. ^(c)See Berens, U. etal., Angew. Chem. Int. (2000) 39. 1981. ^(d)See Marinetti, A. et al.,Synlett (1999) 12, 1975. ^(e)Ligand 22a R = Me; 22b R = Et; 23a R = Me;23b R = i-Pr. ^(f)Enantiomeric excesses were determined by chiral GCusing a Chirasil-VAL III FSOT column.

[0130] Table 6 summarizes the results of Rh(I)-24 complex catalyzedhydrogenation of different dehydroamino acids and some ester derivatives25. For most tri-substituted dehydroamino acids and esters, highselectivity was achieved (95-99% ee). One exception was the substrate inwhich R=p-MeO-phenyl (entry 9), only 88.3% ee was obtained, and thereaction was not complete after 3 h, which is normally enough for mostsubstrates. Tetra-substituted dehydroamino acid was also explored (entry16), but the ee value (88.8%) was a little lower than those for thetri-substituted substrates. Irregardless, the overallenantioselectivities for the Rh(I)-24 catalyzed hydrogenation ofdehydroamino acid derivatives were quite good and comparable with thoseattained with the best chiral bisphosphine systems, especially whenconsidering that among the current C₂-symmetric ferrocenyl-bisphosphineligands, these results are among the best reported to date. SeeMarinetti, A. et al., Synlett (1999) 12, 1975; Berens, U. et al., Angew.Chem. Int. (2000) 39, 1981; Sawamura, M. et al., J. Am. Chem. Soc.(1995) 117, 9602; Kang, J. et al., Tetrahedron Letter (1998) 39, 5523;Perea, J. J. A. et al., Tetrahedron Letter (1998) 39, 8073; Perea, J. J.A. et al., Tetrahedron: Asymmetry (I 999) 10, 375; Nettekoven, U. etal., J. Org. Chem. (1999) 64, 3996. TABLE 6 Rh(I)-24 CatalyzedAsymmetric Hydrogenation of Dehydroamino Acid Derivatives^(a)

Entry Substrate ee (%)^(c) 1 R = H, R′ = H >99^(d) 2 R = H, R′ = CH₃ >993 R = i-Pr, R′ = H >99^(d) 4 R = Ph, R′ = H  94^(d) 5 R = Ph, R′ = CH₃ 96 6 R = p-F—Ph, R′ = H  95^(d) 7 R = p-F—Ph, R′ = CH₃  95 8 R =p-MeO—Ph, R′ = H 9 R = p-MeO—Ph, R′ = CH₃  88^(e,f) 10 R = o-Cl—Ph, R′ =H 11 R = o-Cl—Ph, R′ = CH₃  97 12 R = m-Br—Ph, R′ = H  98^(d) 13 R =m-Br—Ph, R′ = CH₃  97 14 R = 2-naphthyl, R′ = H  98^(d) 15 R =2-naphthyl, R′ = CH₃  97 16

 89

[0131] Hydrogenation of itaconic acid derivatives was also preliminarilyexplored with the same catalytic system as above. The reaction wascarried at rt under 80 psi of H₂ for 12 h. In situ catalyst, [Rh(COD)₂PF₆] (1.0 mol %) and 24 (1.1 mol %), was stirred for 15 min prior tointroduction of substrate and H₂. The reaction went with 100%conversion. The R absolute configuration was assigned by comparison ofoptical rotation with reported data. Enantiomeric excesses weredetermined on the corresponding dimethyl ester by chiral GC using agama-225 column. Excellent results, 99% ee and 96% ee were achieved foritaconic acid 27a and its derivative 27b, respectively.

Example 10 Asymmetric Allylic Alkylation Using Ligands Me-f-KetalPhos(24). Et-f-KetalPhos (28) and Me-KetalPhos (10)

[0132] Palladium compounds with chiral ligands f-KetalPhos and KetalPhosare effective catalyst for asymmetric allylic alkylation of allylicesters. Table 7 lists some experimental results obtained in thisreaction. [Pd(Cl)(C₃H₅)]₂ was used as the catalytic precursor, KOAc andBSA were used in the reaction. The reactions were run in either CH₂Cl₂or THF. With chiral ligand 24, up to 91% ee was obtained. Modificationof Me-f-KetalPhos (24) to Et-f-KetalPhos (28) lead to a higher ee (94%).In CH₂Cl₂, Up to 99% ee was achieved with a palladium catalyst bearingthe Me-ketalPhos (10) ligand. The yields of these reactions are all over95% under the reaction conditions. TABLE 7 Pd. - Catalyzed AsymmetricAllylic Alkylation

Ligand Solvent ee (%) 24 CH₂Cl₂ 91.4 28 CH₂Cl₂ 93.6 28 THF 93.0 10CH₂Cl₂ >99

[0133] The foregoing written description relates to various embodimentsof the present invention. Numerous changes and modifications may be madetherein without departing from the spirit and scope of the invention asdefined in the following claims.

What is claimed is:
 1. A compound of formula A, A′, C and C′, or thecorresponding enantiomer:

wherein: a) R and R² are independently aryl, alkyl, alkyl aryl, arylalkyl, or chiral oxazolino which may be substituted with carboxylicacid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino, ordiphenylphosphino groups; b) R¹ can be H, alkyl, silane, aryl, a watersoluble unit, or a linked polymer chain or inorganic support; and c)

 may be: —(CH₂)_(n)— where n is an integer ranging from 1 to 8;—(CH₂)_(n)X(CH₂)_(m)— wherein n and m are each integers, the same ordifferent, ranging from 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴,divalent aryl, divalent fused aryl, divalent 5-membered ringheterocyclic group, or divalent fused heterocyclic group, wherein R⁴ isaryl, alkyl, substituted aryl, or substituted alkyl; or 1,2-divalentphenyl, 2,2′-divalent 1,1′biphenyl or 2,2′-divalent 1,2′-binapthyl orferrocene, each of which may be substituted with aryl, C₁-C₈ alkyl, F,Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, orSbR⁵ ₂; wherein the substitution on 1,2-divalent phenyl, the ferroceneor biaryl bridge can be independently halogen, alkyl, alkoxyl, aryl,aryloxy, nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonicacids; and R⁵ is hydrogen, C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, or C₁-C₈perfluoroalkyl, aryl; substituted aryl; arylalkyl; ring-substitutedarylalkyl; or —CR³ ₂(CR³ ₂)_(q)X(CR³ ₂)_(p)R¹ wherein q and p areintegers, the same or different, ranging from 1 to 8; R³ is aryl, alkyl,substituted aryl, or substituted alkyl; and X is as defined above.
 2. Acompound according to claim 1, wherein the compound is of formula A orA′, or the corresponding enantiomer.
 3. A compound according to claim 2,wherein the compound is of formula A or A′, or the correspondingenantiomer, wherein R is methyl, ethyl, or benzyl; R¹ is hydrogen orbenzyl; and

is: —(CH₂)_(n)— where n is an integer ranging from 1 to 3; 1,2-divalentphenyl, 2,2′-divalent 1,1′biphenyl, 2,2′-divalent 1,2′binapthyl, orferrocene, each of which may be substituted with alkyl having 1-3 carbonatoms or OR⁵, wherein R⁵ is methyl or ethyl.
 4. A compound according toclaim 3, selected from L1, L3-L5, L7-L8, L10-L12, and L18-L21:


5. A compound according to claim 3, of formula 2:


6. A compound according to claim 3, of formula 3:


7. A compound according to claim 1, wherein the compound is of formula Cor C′ or the corresponding enantiomer.
 8. A compound according to claim7, wherein R is methyl, ethyl, cyclohexyl, or phenyl; R¹ is hydrogen orbenzyl; R² is o-X-phenyl wherein X is hydrogen or a carboxylic acid,alkoxy, hydroxy, alkylthio, thiol, dialkylamino, diphenylphosphino, orchiral oxazolino group.
 9. A compound, according to claim 1, which isselected from structures L26, L28, L29, L30 and L32, represented by theformulas:


10. A compound according to claim 1, represented by the formula (1):


11. A compound of the following formula or its corresponding enantiomer:

wherein: A) R is each C₁-C₈ alkyl, C₁-C₈ alkyl aryl; aryl C₁-C₈ alkyl,aryl, each of which may be substituted with carboxylic acid, alkoxy,hydroxy, C₁-C₈ alkylthio, thiol, dialkylamino, or diphenylphosphino, orchiral oxazoline; and B) R¹ is each H, C₁-C₈ alkyl, silane, aryl, awater soluble unit, or a linked polymer chain or linked inorganicsupport; and C)R² is either R, H, or a symmetrical bidentate structurehaving the formula

 wherein

 is i) —(CH₂)_(n)— where n is an integer from 1 to 8; or ii)—(CH₂)_(n)X(CH₂)_(m)— where n and m are the same or different integersfrom 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴, divalent aryl,divalent fused aryl, divalent 5-membered heterocyclic ring, or divalentfused heterocyclic ring, where R⁴ is C¹-C⁸ alkyl, aryl, substitutedaryl, or substituted C₁-C₈ alkyl; or iii) 1,2-divalent phenyl,2,2′-divalent 1,1′biphenyl, 2,2′-divalent, 1,1′ binapthyl, or ferrocene,each of which may be substituted independently with C₁-C₈ alkyl or aryl,F, Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂,SbR⁵ ₂, nitro, vinyl, substituted vinyl, alkynyl wherein R⁵ is H, C₁-C₈alkyl, substituted C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, C₁-C₈ perfluoroalkyl,aryl or substituted aryl; and wherein Z is a compound selected from thegroup of compounds having the following formula and their correspondingenantiomers:


12. A compound according to claim 11 wherein R is methyl, ethyl, orbenzyl; R¹ is hydrogen or benzyl, and

is: —(CH₂)_(n)— where n is an integer from 1 to 3; 1,2-divalent phenyl,2,2′ divalent 1,1′ biphenyl, 2,2′-divalent 1,2′ binapthyl, or ferrocene,each of which may substituted with C₁-C₃ alkyl or OR⁵, wherein R⁵ ismethyl or ethyl.
 13. A compound according to claim 11 selected from thegroup of compounds of the following formulas and their correspondingenantiomers:


14. A compound according to claim 11 selected from the group ofcompounds of the following formulas and their corresponding enantiomerswherein R is either methyl or ethyl:


15. A compound according to claim 11 selected from the group ofcompounds of the following formulas and their corresponding enantiomerswherein R is either methyl or ethyl:


16. A compound according to claim 11 selected from the group ofcompounds of the following formula and their corresponding enantiomers:


17. A compound selected from the group of compounds of the followingformula:

wherein A) R is C₁-C₈ alkyl, C₁-C₈ alkyl aryl, aryl C₁-C₈ alkyl, oraryl, each of which may be substituted with carboxylic acid, alkoxy,hydroxy, alkylthio, thiol, dialkylamino, diphenylphosphino or chiraloxazoline; and B) R¹ is H, C₁-C₈ alkyl, silane, aryl, a water solubleunit, or a linked polymer chain, or linked inorganic support; and C)R²is either R, H, or a symmetrical bidentate structure having thefollowing formula:

 wherein

 is i) —(CH₂)_(n)— where n is an integer from 1 to 8; or ii)—(CH₂)_(n)X(CH₂)_(m)— where n and m are the same or different integersfrom 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴, divalent aryl,divalent fused aryl, divalent 5-membered heterocyclic ring, or divalentfused heterocyclic ring, where R⁴ is C₁-C₈ alkyl, aryl, substitutedaryl, or substituted alkyl; or iii) 1,2-divalent phenyl, 2,2′-divalent1,1′-biphenyl, 2,2′-divalent, 1,1′-binapthyl, or ferrocene, each ofwhich may be substituted independently with C₁-C₈ alkyl or aryl, F, Cl,Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, SbR⁵ ₂,nitro, vinyl, substituted vinyl, alkynyl wherein R⁵ is H, C₁-C₈ alkyl,substituted C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, C₁-C₈ perfluoroalkyl, arylor substituted aryl; and wherein Z is a compound selected from the groupof compounds having the following formula:


18. A compound according to claim 17 wherein R is methyl, ethyl, orbenzyl; R¹ is hydrogen or benzyl; and the

of R² is: —(CH₂)_(n)— where n is an integer ranging from 1 to 3;1,2-divalent phenyl, 2,2′-divalent 1,1′ biphenyl, 2,2′-divalent 1,2′binapthyl, or ferrocene, each of which may be substituted with C₁-C₃alkyl or OR⁵, wherein R⁵ is methyl or ethyl.
 19. A compound according toclaim 18 selected from the following formulas:


20. A compound according to claim 17 selected from the group ofcompounds of the following formula wherein R is methyl or ethyl:


21. A compound according to claim 17 selected from the group ofcompounds of the following formula and their corresponding enantiomerswherein R is either methyl or ethyl:


22. A compound according to claim 17 selected from the group ofcompounds of the following formula wherein R is either methyl or ethyl:


23. A catalyst comprising a compound in the form of a complex with atransition metal wherein said compound is selected from compoundsrepresented by the formula:


24. A catalyst according to claim 23, wherein the transition metal isrhodium, iridium, ruthenium, nickel, or palladium.
 25. A catalystaccording to claim 24, wherein said compound is a complex with acompound selected from the group consisting of: Pd₂(DBA)₃, Pd(OAc)₂;[Rh(COD)Cl]₂, [Rh(COD)₂]X, Rh(acac)(CO)₂; RuCl₂(COD),Ru(COD)(methylallyl)₂, Ru(Ar)Cl₂, wherein Ar is an aryl group,unsubstituted or substituted with an alkyl group; [Ir(COD)Cl]₂,[Ir(COD)₂]X; and Ni(allyl)X; wherein X is a counterion.
 26. A catalystaccording to claim 25, wherein X is selected from the group consistingof: Fl⁻, Cl⁻, Br⁻, I⁻, BF₄ ⁻, ClO₄ ⁻, SbF₆ ⁻, CF₃SO₃ ^(—), and PF₆ ⁻.27. A catalyst according to claim 26 wherein X is PF₆ ⁻.
 28. A catalystaccording to claim 24 wherein the transition metal is Ru or Rh.
 29. Acatalyst according to claim 28 wherein the transition metal is Rh.
 30. Acatalyst according to claim 23, wherein the catalyst comprises:Ru(RCOO)₂(diphosphine), RuX₂(diphosphine),Ru(methylallyl)₂(diphosphine), Ru(aryl group)X₂(diphosphine),Rh(RCOO)₂(diphosphine), RhX₂(diphosphine), Rh(methylallyl)₂ diphosphine,or Rh(aryl group)X₂ (diphosphine) and X is halogen.
 31. A catalystaccording to claim 23 for asymmetric hydrogenation of a ketone, imine,or olefin, comprising: a complex of compounds 2 or 3 with a Rh compoundselected from the group consisting of: [Rh(COD)Cl]₂ and [Rh(COD)₂]X,wherein X is selected from the group consisting of: BF₄, ClO₄, SbF₆,CF₃SO₃.:


32. A catalyst according to claim 23 comprising a transition metalcomplex of a compound of the following formula or its enantiomer:

wherein: (A) R is each C₁-C₈ alkyl, C₁-C₈ alkyl aryl; aryl C₁-C₈ alkyl,aryl, each of which may be substituted with carboxylic acid, alkoxy,hydroxy, C₁-C₈ alkylthio, thiol, dialkylamino, or diphenylphosphino, orchiral oxazoline; and (B) R¹ is each H, C₁-C₈ alkyl, silane, aryl, awater soluble unit, or a linked polymer chain or linked inorganicsupport; and (C)R² is either R, H, or a symmetrical bidentate structurehaving the formula

(i) —(CH₂)_(n)— where n is an integer from 1 to 8; or (ii) —(CH₂)_(n) X(CH₂)_(m)— where n and m are the same or different integers from 1 to 8,and X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴, divalent aryl, divalent fused aryl,divalent 5-membered heterocyclic ring, or divalent fused heterocyclicring, where R⁴ is C¹-C⁸ alkyl, aryl, substituted aryl, or substitutedC₁-C₈ alkyl; or (iii) 1,2-divalent phenyl, 2,2′-divalent 1,1′biphenyl,2,2′-divalent, 1,1′ binapthyl, or ferrocene, each of which may besubstituted independently with C₁-C₈ alkyl or aryl, F, Cl, Br, I, COOR⁵,SO₃R⁵, PO₃R⁵ ₂, OR¹, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, SbR⁵ ₂, nitro, vinyl,substituted vinyl, alkynyl wherein R⁵ is H, C₁-C₈ alkyl, substitutedC₁-C₈ alkyl, C₁-C₈ fluoroalkyl, C₁-C₈ perfluoroalkyl, aryl orsubstituted aryl; and wherein Z is a compound selected from the group ofcompounds having the following formula and their correspondingenantiomers:


33. A catalyst according to claim 23, wherein each R¹ is independentlyselected from the group consisting of: methyl and ethyl groups.
 34. Acatalyst according to claim 23, wherein the transition metal complex isderived from a compound of the following formula or its enantiomer:


35. A catalyst according to claim 23, wherein the transition metalcomplex is derived from a compound of the following formula or itsenantiomer:


36. A catalyst according to claim 23 comprising a transition metalcomplex of a compound of the following formula or its enantiomer:

wherein A) R is C₁-C₈ alkyl, C₁-C₈ alkyl aryl, aryl C₁-C₈ alkyl, aryl,each of which may be substituted with carboxylic acid, alkoxy, hydroxy,alkylthio, thiol, dialkylamino, diphenylphosphino or chiral oxazoline;and B) the ring component O

O represents a protected diol, a crown ether linkage, —O—C₁-C₈ alkyl-O—wherein the alkyl group is linked to a polymer, —O—(CH₂CH₂)_(n)—O—wherein n is an integer ranging from 1 to 8 and the methylene groups areoptionally substituted by C₁-C₈ alkyl, or O—W-0, where W is BR⁹, POR⁹,PO(OR⁹), SO₂, CO, or Si(R⁹)₂;  where R⁹ is C₁-C₈ alkyl, aryl, C₁-C₈alkyl aryl, or aryl C₁-C₈ alkyl, alkoxy, hydroxy, alkylthio, thio,alkylamino, dialkylamino; and C)R² is either R, H, phenyl or asymmetrical bidentate structure having the formula

i) —CH₂)_(n)— where n is an integer from 1 to 8; or ii)—(CH₂)_(n)X(CH₂)_(m) where n and m are the same or different integersfrom 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴, divalent aryl,divalent fused aryl, divalent 5-membered heterocyclic ring, or divalentfused heterocyclic ring, where R⁴ is C¹—C⁸ alkyl, aryl, substitutedaryl, or substituted alkyl; or iii) 1,2-divalent phenyl, 2,2′-divalent1,1′biphenyl, 2,2′-divalent, 1,1′ binapthyl, or ferrocene, each of whichmay be substituted independently with C₁ —C₈ alkyl or aryl, F, Cl, Br,I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, SbR⁵ ₂, nitro,vinyl, substituted vinyl, alkynyl wherein R⁵ is H, C₁-C₈ alkyl,substituted C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, C₁-C₈ perfluoroalkyl, arylor substituted aryl; and wherein Z is a compound selected from the groupof compounds having the following formulas and their correspondingenantiomers:


37. A process for preparing a compound of formula A, represented by theformula:

said process comprising: reacting a compound of formula B* with aphosphine to form compound B:

and thereafter reacting compound B with an acid to form compound A;wherein the phosphine is

 ; A) R is aryl, C₁-C₈ alkyl, C₁-C₈ alkyl aryl, or aryl C₁-C₈ alkyl,which may be substituted with carboxylic acid, alkoxy, hydroxy, C₁-C₈alkylthio, thiol, dialkylamino, diphenylphosphino, or chiral oxazolinogroups; B) the ring component

 represents a protected diol, a crown ether linkage, or—O—(CH₂CH₂)_(n)—O— wherein n is an integer ranging from 1 to 8 and themethylene groups are optionally substituted by alkyl or linked to apolymer; and C)

 may be: —(CH₂)_(n)— where n is an integer ranging from 1 to 8;—(CH₂)_(n)—X—(CH₂)_(n)— wherein n, m are each integers, the same ordifferent, ranging from 1 to 8; or 1,2-divalent phenyl, 2,2′-divalent1,1′ biphenyl or 2,2′-divalent 1,2′binapthyl or ferrocene, each of whichmay be substituted with aryl or substituted aryl, or alkyl having 1-8carbon atoms, heteroatom groups such as F, Cl, Br, I, COOR⁵, SO₃R⁵,PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, or SbR⁵ ₂, wherein thesubstitution on 1,2-divalent phenyl, the ferrocene or biaryl bridge canbe independently halogen, C₁-C₈ alkyl, alkoxyl, aryl, aryloxy, nitro,amino, vinyl, substituted vinyl, alkynyl, or sulfonic acids; and R⁵ ishydrogen, C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, or C₁-C₈ perfluoro, aryl;substituted aryl; aryl C₁-C₈ alkyl; ring-substituted arylalkyl; or CR³₂(CR³ ₂)_(q)X(CR³ ₂)_(p)R¹ wherein q and p are integers, the same ordifferent, ranging from 1 to 8; X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴,divalent aryl, divalent fused aryl, divalent 5-membered ringheterocyclic group, or divalent fused heterocyclic group, wherein R³ andR⁴ are aryl, C₁-C₈ alkyl, substituted aryl and substituted alkyl groups.38. A process according to claim 37 wherein: R is C₁-C₄ alkyl; the ringcomponent

 represents a protected diol; and

 is unsubstituted or substituted 1,2-divalent phenyl.
 39. A processaccording to claim 38 wherein R is methyl or ethyl, the ring component

is —O—C(CH₃)₂—O— and

is unsubstituted 1,2-divalent phenyl.
 40. A process comprisingsubjecting a substrate to an asymmetric reaction in the presence of acatalyst comprising a chiral ligand represented by the formula A, A′, B,B′, C, C′, D, or D′, or the corresponding enantiomer:

wherein: a) R and R² are independently aryl, alkyl, alkyl aryl, arylalkyl, or chiral oxazolino which may be substituted with carboxylicacid, alkoxy, hydroxy, alkylthio, thiol, dialkylamino, ordiphenylphosphino groups; b) R¹ can be H, alkyl, silane, aryl, a watersoluble unit, or a linked polymer chain or inorganic support; c) thering component

 represents a protected diol, a crown ether linkage, —O-alkyl-O— whereinthe alkyl group is linked to a polymer, or —O—(CH₂CH₂—O)_(n)— wherein nis an integer ranging from 1 to 8 and the methylene groups areoptionally substituted by C₁-C₈ alkyl; and d)

 may be: —(CH₂)_(n)— where n is an integer ranging from 1 to 8;—(CH₂)_(n)X(CH₂)_(m)— wherein n and m are each integers, the same ordifferent, ranging from 1 to 8, and X is O, S, NR⁴, PR⁴, AsR⁴, SbR⁴,divalent aryl, divalent fused aryl, divalent 5-membered ringheterocyclic group, or divalent fused heterocyclic group, wherein R⁴ isaryl, alkyl, substituted aryl, or substituted alkyl; or 1,2-divalentphenyl, 2,2′-divalent 1,1′biphenyl or 2,2′-divalent 1,2′binapthyl orferrocene, each of which may be substituted with aryl, C1-C8 alkyl, F,Cl, Br, I, COOR⁵, SO₃R⁵, PO₃R⁵ ₂, OR⁵, SR⁵, NR⁵ ₂, PR⁵ ₂, AsR⁵ ₂, orSbR⁵ ₂, wherein: the substitution on 1,2-divalent phenyl, the ferroceneor biaryl bridge can be independently halogen, alkyl, alkoxyl, aryl,aryloxy, nitro, amino, vinyl, substituted vinyl, alkynyl, or sulfonicacids; and R⁵ is hydrogen, C₁-C₈ alkyl, C₁-C₈ fluoroalkyl, or C₁-C₈perfluoroalkyl, aryl; substituted aryl; arylalkyl; ring-substitutedarylalkyl; or —CR³ ₂(CR³ ₂)_(q)X(CR³ ₂)_(p)R¹ wherein q and p areintegers, the same or different, ranging from 1 to 8; R³ is aryl, alkyl,substituted aryl, or substituted alkyl; and X is as defined above;wherein said asymmetric reaction is a hydrogenation, hydride transfer,hydrosilylation, hydroboration, hydrovinylation, olefin metathesis,hydroformylation, hydrocarboxylation, allylic alkylation,cyclopropanation, Diels-Alder, Aldol, Heck [m+n] cycloaddition, orMichael addition reaction.
 41. A process according to claim 40, whereinsaid asymmetric reaction comprises asymmetric hydrogenation of a ketone,imine, enamide, or olefin.
 42. A process according to claim 40, whereinsaid asymmetric reaction comprises Rh(I)-catalyzed hydrogenation of adehydroamino acid or an ester thereof.